Journal
DEVELOPMENT
Volume 140, Issue 23, Pages 4683-+Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/dev.102798
Keywords
Cell cycle; Proliferation; Regeneration; Mouse
Categories
Funding
- National Institutes of Health (NIH) [R56DK094865, 1U01HL087365, 5T32HL007676-23]
- Vivian L. Smith Foundation
- Cancer Prevention Research Institute of Texas (CPRIT) [P120138 IIRA]
- American Heart Association (AHA) [AHA10POST4140029, AHA12POST11760019, AHA NCRP SDG 0930240N]
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Heart failure due to cardiomyocyte loss after ischemic heart disease is the leading cause of death in the United States in large part because heart muscle regenerates poorly. The endogenous mechanisms preventing mammalian cardiomyocyte regeneration are poorly understood. Hippo signaling, an ancient organ size control pathway, is a kinase cascade that inhibits developing cardiomyocyte proliferation but it has not been studied postnatally or in fully mature adult cardiomyocytes. Here, we investigated Hippo signaling in adult cardiomyocyte renewal and regeneration. We found that unstressed Hippo-deficient adult mouse cardiomyocytes re-enter the cell cycle and undergo cytokinesis. Moreover, Hippo deficiency enhances cardiomyocyte regeneration with functional recovery after adult myocardial infarction as well as after postnatal day eight (P8) cardiac apex resection and P8 myocardial infarction. In damaged hearts, Hippo mutant cardiomyocytes also have elevated proliferation. Our findings reveal that Hippo signaling is an endogenous repressor of adult cardiomyocyte renewal and regeneration. Targeting the Hippo pathway in human disease might be beneficial for the treatment of heart disease.
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